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Anticholinergic poisoning [keywords]
- Discovery of subtype selective muscarinic receptor antagonists as alternatives to atropine using in silico pharmacophore modeling and virtual screening methods. [Journal Article]
- Bioorg Med Chem 2013 May 1; 21(9):2651-62.
Muscarinic acetylcholine receptors (mAChRs) have five known subtypes which are widely distributed in both the peripheral and central nervous system for regulation of a variety of cholinergic functions. Atropine is a well known muscarinic subtype non-specific antagonist that competitively inhibits acetylcholine (ACh) at postganglionic muscarinic sites. Atropine is used to treat organophosphate (OP) poisoning and resulting seizures in the warfighter because it competitively inhibits acetylcholine (ACh) at the muscarinic cholinergic receptors. ACh accumulates due to OP inhibition of acetylcholinesterase (AChE), the enzyme that hydrolyzes ACh. However, atropine produces several unwanted side-effects including dilated pupils, blurred vision, light sensitivity, and dry mouth. To overcome these side-effects, our goal was to find an alternative to atropine that emphasizes M1 (seizure prevention) antagonism but has minimum M2 (cardiac) and M3 (e.g., eye) antagonism so that an effective less toxic medical countermeasure may be developed to protect the warfighter against OP and other chemical warfare agents (CWAs). We adopted an in silico pharmacophore modeling strategy to develop features that are characteristics of known M1 subtype-selective compounds and used the model to identify several antagonists by screening an in-house (WRAIR-CIS) compound database. The generated model for the M1 selectivity was found to contain two hydrogen bond acceptors, one aliphatic hydrophobic, and one ring aromatic feature distributed in a 3D space. From an initial identification of about five hundred compounds, 173 compounds were selected through principal component and cluster analyses and in silico ADME/Toxicity evaluations. Next, these selected compounds were evaluated in a subtype-selective in vitro radioligand binding assay. Twenty eight of the compounds showed antimuscarinic activity. Nine compounds showed specificity for M1 receptors and low specificity for M3 receptors. The pKi values of the compounds range from 4.5 to 8.5nM in comparison to a value of 8.7nM for atropine. 2-(diethylamino)ethyl 2,2-diphenylpropanoate (ZW62841) was found have the best desired selectivity. None of the newly found compounds were previously reported to exhibit antimuscarinic specificity. Both theoretical and experimental results are presented.
- Successful management of olanzapine-induced anticholinergic agitation and delirium with a continuous intravenous infusion of physostigmine in a pediatric patient. [Case Reports, Journal Article]
- Clin Toxicol (Phila) 2013 Mar; 51(3):162-6.
Physostigmine effectively reverses anticholinergic delirium. However, continuous IV infusion of physostigmine is rarely used due to concern for cardiotoxicity and signs of cholinergic excess such as seizures, nausea, and vomiting. We report the successful use of continuous IV physostigmine in a 6-year-old boy with anticholinergic delirium. A 6-year-old, 30-kg boy with attention deficit hyperactivity disorder (ADHD) ingested 15-20 olanzapine (5 mg) tablets. He was agitated and was treated with lorazepam at a local hospital. His heart rate was 148 beats per min; respiratory rate, 32 breaths per minute; blood pressure, 111/70 mmHg; temperature, 96.8°F, and O2 saturation of 98% on room air. His pupils were 5-6 mm, and his skin was warm and initially flushed. Blood chemistry results were normal. A 12-lead ECG showed sinus tachycardia with normal QRS and QT intervals. The agitation worsened and did not respond to benzodiazepines. The patient was then given a dose of 0.6 mg physostigmine (0.02 mg/kg) intravenously with reversal of the agitation. But the effect only lasted 45 min requiring administration of a second bolus of 0.6 mg (0.02 mg/kg). A physostigmine intravenous infusion was administered at a rate of 0.5 mg/h (0.0167 mg/kg/h). Overnight, the patient became more agitated. The physostigmine was discontinued, and IV dexmedetomidine (0.2 μg/kg/h) was started at 21:00. The patient became over-sedated with pinpoint pupils resulting in discontinuation of the dexmedetomidine at 04:00. The patient again became agitated and developed visual hallucinations. Three 1-mg (0.03 mg/kg) boluses of physostigmine were administered over 45 min, and the physostigmine infusion was restarted at a rate of 1 mg/h (0.03 mg/kg/h) for 16.5 h. He received 19.5 mg of physostigmine with no return of anticholinergic symptoms and no signs of cholinergic excess except for a tremor that resolved when the infusion was stopped. He was discharged home without further sequelae. There are few publications describing a continuous infusion of physostigmine to reverse anticholinergic delirium. Our patient received a total dose of 25.5 mg with complete resolution of symptoms. We report the successful use of continuous infusion of physostigmine to reverse anticholinergic delirium in a pediatric patient who unintentionally ingested olanzapine.
- [Urticaria multiforme is a variation of urticaria, which imitates erythema multiforme]. [Case Reports, English Abstract]
- Ugeskr Laeger 2013 Feb 11; 175(7):436-7.
A 21-month-old boy developed urticaria multiforme during the course of a presumed pneumonia, which was treated with imacillin. At admission to hospital he was initially considered to have erythema multiforme, but the correct diagnosis was soon established as urticaria multiforme. He had a good response to antihistamines. The diagnostic differences between urticaria multiforme and erythema multiforme are presented in this case report.
- Chinese herbal medicine-induced anticholinergic poisoning in Hong Kong. [Journal Article]
- Hong Kong Med J 2013 Feb; 19(1):38-41.
To study the epidemiology, causes, and clinical course of Chinese herbal medicine-induced anticholinergic poisoning in Hong Kong.Case series.Hong Kong.All case histories of Chinese herbal medicine-induced anticholinergic poisoning (with laboratory confirmation) recorded by the Hong Kong Poison Information Centre over a 93-month period were accessed for analysis.During the relevant period, 22 clusters of Chinese herbal medicine-induced anticholinergic poisoning involving 32 patients were retrieved. The commonest clinical features were mydriasis (n=32, 100%) and confusion (n=24, 75%). No gastro-intestinal decontamination was performed. None of these patients underwent intubation, defibrillation, cardioversion, pacing, fluid resuscitation, inotropic support or dialysis. Of the 32 patients, 17 (53%) were treated with physostigmine because of confusion, three of whom had previously received intravenous benzodiazepines. No patient could be effectively treated with benzodiazepines alone. There was no mortality, and all the patients were discharged within 3 days. None of them re-attended the emergency department within 1 week of discharge. The commonest cause was the substitution of flos campsis (Campsis grandiflora) by the flower of the Datura species (7 clusters [32%] in 10 patients).Mydriasis and confusion were the commonest clinical features of Chinese herbal medicine-induced anticholinergic poisoning in Hong Kong. Physostigmine was frequently used in the treatment; benzodiazepines appeared ineffective. The commonest cause was the substitution of flos campsis (Campsis grandiflora) by the flower of the Datura species.
- Phase II study of magnesium sulfate in acute organophosphate pesticide poisoning. [Clinical Trial, Phase II, Comparative Study, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't]
- Clin Toxicol (Phila) 2013 Jan; 51(1):35-40.
Acute organophosphorus (OP) poisoning is relatively common and a major cause of death from poisoning in developing countries. Magnesium has been shown to be of benefit in animal models.We conducted a phase II study of bolus doses of (MgSO4) in 50 patients with acute organophosphate poisoning. Patients eligible for inclusion had ingested OP and had cholinergic symptoms consistent with moderate or severe poisoning. All patients received standard care of atropinization titrated to control muscarinic symptoms and pralidoxime. The trial was run in 4 sequential groups of patients. Participants in each group received a different total dose of MgSO4 (20%) administered as intermittent bolus doses infused over 10-15 min or placebo. There was one control patient for every 4 patients who received MgSO4. Group A (16 patients) received a total of 4 gm MgSO4 as a single bolus, group B (8 patients) received 8 gm (in two 4 gm doses q4H), group C (8 patients) received 12 gm (in three 4 gm doses q4H) group D (8 patients) received 16 gm (in four 4 gm doses q4H) and control (10 patients) received placebo). Patients were closely monitored for any adverse reaction like significant clinical neuromuscular disturbance and respiratory depression.No adverse reactions to magnesium were observed. The 24 hour urinary magnesium concentration were statistically different between 16 gm (234.74 ± 74.18 mg/dl) and control (118.06 ± 30.76 mg/dl) (p = 0.019), while it was much lower than the 80% of the intravenous magnesium load. Six patients died in control group compared to 3 in 4 gm, 2 in 8 gm and 1 in 12 gm group. There was no mortality in 16 gm group.Magnesium was well tolerated in this study. Larger studies are required to examine for efficacy.
- Diagnosis and treatment of drug-induced hyperthermia. [Journal Article]
- Am J Health Syst Pharm 2013 Jan 1; 70(1):34-42.
The etiology, pathophysiology, clinical presentation, and management of drug-induced hyperthermia (DIH) syndromes are reviewed.DIH syndromes are a rare and often overlooked cause of body temperature elevation and can be fatal if not recognized promptly and managed appropriately. There are five major DIH syndromes: (1) neuroleptic malignant syndrome, (2) serotonin syndrome, (3) anticholinergic poisoning, (4) sympathomimetic poisoning, and (5) malignant hyperthermia. The differential diagnosis of DIH syndromes can be challenging because symptoms are generally nonspecific, ranging from blood pressure changes and excessive sweating to altered mental status, muscle rigidity, convulsions, and metabolic acidosis. Evidence from the professional literature (per a MEDLINE search for articles published through November 2011) indicates that few currently available treatment options can reduce the duration of hyperthermia; therefore, prompt identification of the provoking agent based on the patient's medication history, the clinical presentation, and the timing of symptom onset is essential to determine the appropriate treatment and mitigate potentially life-threatening sequelae. For all DIH syndromes, appropriate management includes the immediate discontinuation of the suspected offending agent(s) and supportive care (external cooling, volume resuscitation as needed); in some cases, pharmacologic therapy (e.g., a benzodiazepine, bromocriptine, dantrolene) may be appropriate, with the selection of a specific agent primarily determined by the medication history and suspected DIH syndrome.DIH is a hypermetabolic state caused by medications and other agents that alter neurotransmitter levels. The treatment of DIH syndromes includes supportive care and pharmacotherapy as appropriate.
- [Prolonged toxic coma and anisocoria secondary to doxepin, lorazepam and phenobarbital poisoning--case study]. [Case Reports, English Abstract, Journal Article]
- Przegl Lek 2012; 69(8):624-6.
Doxepin is a tricyclic antidepressant from the group of dibenzoxepines. Apart from the antidepressant effect, it has also the sedative and anxiolytic effect, so it is used in the treatment of anxiety disorder in the course of psychosis, organic diseases and alcoholism. Doxepin increases concentration of norepinephrine and serotonin in the brain by preventing inactivation and blocking their reuptake. In addition, the drug has an antagonistic effect on receptors in CNS (muscarinic M1, histamine H1, alpha-1adrenergic, serotonergic 5-HT2) and also blocks sodium and potassium channels in cardiomyocytes. In this paper we present a case of severe poisoning by various drugs, including doxepin. The dominating symptom was prolonged toxic coma. Slow return of consciousness was observed from the fifth day after intoxication, logical verbal contact with the patient was possible on the seventh day. It seems that this symptom results from the pharmacokinetic properties of doxepin as well as the high drug dose and a synergistic effect of lorazepam and phenobarbital. Transient anisokoria was an unusual symptom that appeared in the course of intoxication. The patient was examined by a neurologist and underwent CT of the head twice - no organic causes were revealed. This phenomenon can be explained by physiological anisokoria, caused by asymmetry in the sympathetic innervation of pupil rectractor muscle, exacerbated by a complete parasympathetic conduction block as a result of anticholinergic action of doxepin. Tricyclic antidepressants are often used by patients for the purpose of suicide. Because of the serious cardiological and neurological symptoms the course of doxepin intoxication may be severe.
- Acetaminophen/diphenhydramine overdose in profound hypothermia. [Case Reports, Journal Article]
- Clin Toxicol (Phila) 2013 Jan; 51(1):50-3.
There are few reports of acetaminophen overdose in hypothermic patients and even fewer reports describing profound hypothermia. The kinetics, risk of hepatotoxicity, and the possible dose adjustments to N-acetylcysteine (NAC) therapy are not known in this setting.A 37-year-old female was found unconscious outside in December and was brought by ambulance to a tertiary care Emergency Department (ED) following a presumed overdose of acetaminophen and diphenhydramine. She later confirmed the ingestion and reported the ingestion had occurred approximately 18 hours prior to being found. On arrival, she was profoundly hypothermic, with a core rectal temperature of 17°C. Her initial serum acetaminophen concentration was 232 mcg/mL 19 hours post ingestion of a reported dose of approximately 50 grams of acetaminophen and 2.5 grams of diphenhydramine. Active rewarming was started immediately and IV NAC was initiated using the standard treatment protocol. The patient did not develop serious signs of hepatic injury or NAC toxicity. The patient's AST and ALT peaked 12 hours after admission at 84 IU/L (ref 10-37 U/L) and 104 IU/L (ref 12-78 U/L), respectively. Her INR peaked 2 hours after admission at 1.46 (ref < 1.2).Despite the significant ingestion of acetaminophen, delayed presentation, prolonged period of decreased responsiveness, and profound hypothermia, the patient did not develop any signs/symptoms of liver injury. NAC was administered in a standard dose during her rewarming period without apparent toxicity. The patient's absorption and/or metabolism of acetaminophen were likely slowed by her hypothermia and possibly by the anticholinergic coingestant. Initiation of IV NAC at a standard dose was apparently safe and effective in preventing hepatotoxicity as the patient was rewarmed.Profound hypothermia may be protective of hepatic injury in acetaminophen overdose. Delayed absorption from the coingestant, diphenhydramine, may also have played a role. IV NAC was given in a standard dose without apparent toxicity in the setting of profound hypothermia. Lastly, IV NAC, in standard dosing, appeared to be effective in preventing hepatotoxicity during rewarming in a patient with a potentially hepatotoxic concentration of acetaminophen with a coingestion of the anticholinergic agent, diphenhydramine.
- Penehyclidine hydrochloride: a potential drug for treating COPD by attenuating Toll-like receptors. [Journal Article, Research Support, Non-U.S. Gov't, Review]
- Drug Des Devel Ther 2012.:317-22.
The aim of this review was to evaluate and summarize the available scientific information on penehyclidine hydrochloride (PHC) for the treatment of chronic obstructive pulmonary disease (COPD) as a result of its ability to attenuate Toll-like receptors. Penehyclidine hydrochloride is an anticholinergic drug manufactured in China, with both antimuscarinic and antinicotinic activity. PHC is used widely in the clinic as a reversal agent in cases of organic phosphorus poisoning and soman poisoning, but also may also have an important role as a bronchodilator in the treatment of obstructive airway disease, including asthma and, in particular, COPD.Our bibliographic sources included the CAPLUS, MEDLINE, REGISTRY, CASREACT, CHEMLIST, CHEMCATS, and CNKI databases, updated to September 2012. In order to assess the data in detail, we used the search terms "penehyclidine hydrochloride," "COPD," "muscarinic receptor," and "toll-like receptors." Papers were restricted to those published in the English and Chinese languages, and to "paper" and "review" as the document type. Patents were also reviewed.Our survey mainly yielded the results of research on PHC and the mechanisms of COPD. COPD is a preventable and treatable disease with some significant extrapulmonary manifestations that may contribute to its severity in some patients. Recently, it has been shown that muscarinic receptors may interact with Toll-like receptors. Basic and clinical studies of the relationship between the mechanism of action and the effects of PHC in the respiratory tract have been studied by a number of laboratories and institutions. The main advantages of PHC are that it has few M(2) receptor-associated cardiovascular side effects and attenuates Toll-like receptors.PHC may be a promising candidate agent in the treatment of COPD in the future because of its ability to attenuate Toll-like receptors. This review should be of help to those intending to research this topic further.
- Efficacy of the GluK1/AMPA receptor antagonist LY293558 against seizures and neuropathology in a soman-exposure model without pretreatment and its pharmacokinetics after intramuscular administration. [Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.]
- J Pharmacol Exp Ther 2013 Jan; 344(1):133-40.
Control of brain seizures after exposure to nerve agents is imperative for the prevention of brain damage and death. Animal models of nerve agent exposure make use of pretreatments, or medication administered within 1 minute after exposure, in order to prevent rapid death from peripheral toxic effects and respiratory failure, which then allows the testing of anticonvulsant compounds. However, in a real-case scenario of an unexpected attack with nerve agents, pretreatment would not be possible, and medical assistance may not be available immediately. To determine if control of seizures and survival are still possible without pretreatment or immediate pharmacologic intervention, we studied the anticonvulsant efficacy of the GluK1 (GluR5)/α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist (3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl]decahydroisoquinoline-3-carboxylic acid (LY293558) in rats that did not receive any treatment until 20 minutes after exposure to the nerve agent soman. We injected LY293558 intramuscularly, as this would be the most likely route of administration to humans. LY293558 (15 mg/kg), injected along with atropine and the oxime HI-6 at 20 minutes after soman exposure, stopped seizures and increased survival rate from 64% to 100%. LY293558 also prevented neuronal loss in the amygdala and hippocampus, and reduced neurodegeneration in a number of brain regions studied 7 days after soman exposure. Analysis of the LY293558 pharmacokinetics after intramuscular administration showed that this compound readily crosses the blood-brain barrier. There was good correspondence between the time course of seizure suppression by LY293558 and the brain levels of the compound.